N-benzylindole and benzopyrazole derivatives with anti-asthmatic, anti-allergic, anti-inflammatory and immunemodulating effect

ABSTRACT

The N-benzylindole- and benzopyrazole derivatives of the general formula 1 ##STR1## possess anti-asthmatic, anti-allergic, anti-inflammatory and immunomodulating effect and are suitable for the preparation of medicaments.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to N-benzylindole- and benzopyrazole derivativeshaving anti-asthmatic, anti-allergic, anti-inflammatory andimmunomodulating effects.

2. Background Information

Indole derivatives have many uses as synthetic building blocks for thesynthesis of drugs, for example the drugs indomethacin and acemethacinhave an N-substituted indole skeleton.

Indomethacin is the prototype of compounds having a predominantlyanti-inflammatory and anti-rheumatic effect.

An indazole derivative that can be cited is the substance bendazac whichhas an anti-inflammatory effect; the synthesis of the substance, IUPACname [(1-benzyl-1H-indazole-3-yl)oxy]acetic acid, is described in US PS3 470 194.

DE-OS 42 25 756 and EP 392 317 describe benzimidazoles which constituteangiotensin antagonists, in particular angioterlsin-II antagonists.

DE-OS 27 31 647 describes 1,3-benzothiolanes and their pharmaceuticallyuseful salts.

Colantti (Chim. Ther 6(5), 367-79) describe indole derivatives whichhave coccidiostatic properties.

Clark et al (J. Med. Chem, 36 (18), 264-57) describe1H-indole-3-carboxamides substituted by quinuclidyl radicals andderivatives at the acid amide nitrogen. These compounds are 5HT₃antagonists and can, for example, be used as anti-emetics.

EP 490 263 describes N-methyl-indole derivatives as 5-HT-antagonists.

EP 485 962 describes N-methyl-indole derivatives as S₃ -receptorantagonists.

WO 88/5432 describes N-alkyl substituted 3-indole-carboxylic acidderivatives as diuretics and cardiovascularly active substances.

WO 93/2062 also describes N-alkyl-substituted 3-indole carboxylic acidamides, in which the amide nitrogen is substituted by a heterocyclicsystem, such as a tetrazole ring or a substituted tetrazole ring.

EP 580 502 describes 3-(hydroxybenzylidenyl)-indoline-2-one-derivativeswith an anti-inflammatory, analgesic, anti-arteriosclerotic andanti-asthmatic effect. The compounds, which can be present as anE/Z-isomer mixture, inhibit LTB₄ synthesis.

The compounds carry various substituents at the indoline nitrogen; thereis a keto- or thioketo group at the 2-carbon atom of the indoline ring.

SUMMARY OF THE INVENTION

It is the object of the invention to provide novel compounds which havean anti-asthmatic, anti-allergic, anti-inflammatory and immunemodulatingeffect; processes are also described for the preparation of thecompounds and of drugs that can be obtained from the compounds.

The object of the invention therefore comprises compounds of the generalformula 1 ##STR2## having the following meanings: R¹ =hydrogen, (C₁-C₆)alkyl, where the alkyl group can be straight-chained or branched andcan be substituted once or several times by halogen, phenyl, which forits part can be substituted once or several times by halogen, (C₁-C₆)alkyl, (C₃ -C₇)cycloalkyl, carboxyl groups, esterified carboxylgroups, trifluoromethyl groups, trichloromethyl groups, hydroxyl groups,methoxy groups, ethoxy groups, benzyloxy groups, benzyl groups orbenzoyl groups, 2- or 3-thienyl, 2-quinolyl, 2-, 3- or 4-pyridyl which,for its part, can be substituted once or several times by halogen, (C₁-C₄)alkyl groups or (C₁ -C₄)alkoxy groups, (C₃ -C₇)cycloalkyl, aryl, forexample phenyl or naphthyl, heteroaryl, for example 2-, 3- or 4-pyridyl,2- or 8-quinolyl, 2-thienyl or 1,3 or 8 isoquinolyl, where aryl orheteroaryl can be substituted once or several times by halogen, (C₁-C₄)alkyl, (C₁ -C₄)alkoxy, hydroxy, thiol groups, thioether groups (C₁-C₄)alkanoyl groups, CN, --COOH, --CF₃, NO₂, (C₁ -C₃)alkoxycarbonyl, anamino group of the general formula ##STR3## or aroyl, with aryl in themeaning stated. R² and R³ can be the same or different and can representhydrogen, (C₁ -C₆)alkyl, straight-chained or branched, (C₃-C₇)cycloalkyl, (C₁ -C₆)alkanoyl, (C₁ -C₆)alkoxy, halogen, benzyloxy,hydroxy, in addition R² and R³ can represent the nitro group, the aminogroup, which can be substituted as herein before described, the methoxygroup and carbamic acid esters, which are linked to the aromaticringsystem by the N-atom,

W can represent CH or N,

Y can represent O, S or a single bond in such a manner that theheterocyclic system is directly associated with the group ##STR4## X canrepresent CH or N, furthermore, when Y stands for a single bond in sucha way that the heterocyclic system is directly associated with the group##STR5## X can represent a >C═ group, where a single bond from thegroup >C═, which is only saturated by one hydrogen atom in formula 1, isnow linked via a methylene group to the nitrogen atom of the group NR⁶R⁷ of R⁵, and where furthermore, if R⁶ and R⁷ are equal with hydrogen,this hydrogen is replaced

G can be(i)= ##STR6## or (ii)= ##STR7## or (iii)=R¹⁴ where, in the caseof G=(i)

R⁴ =hydrogen, (C₁ -C₆)alkyl, where the alkyl group can bestraight-chained or branched, (C₃ -C₇)cycloalkyl,

n=1-6

m=0 or 1 ##STR8## R⁵ can represent N-(C₁ -C₆)alkyl-2-pyrrolidinyl or theradical ##STR9## where R⁶ and R⁷ can be the same or different and caneither represent H, (C₁ -C₆)alkyl, quinolyl, phenyl which can besubstituted with pyridylmethyl or the pyridine skeleton, where thepyridine can optionally be linked to one of the ring carbon atoms and besubstituted with the radicals R⁸ and R⁹ which can be the same ordifferent and as substituents R⁸ and R⁹ can have the the meaning (C₁-C₆)alkyl, where the alkyl group can be straight-chained or branched,(C₃ -C₇)cycloalkyl, (C₁ -C₆)alkoxy, NO₂, NH2, ethoxycarbonylamino orphenoxycarbonylamino,

In addition, R⁶ ₁, R⁷ and the N-atom to which they are link, can form apiperazine ring-system of formula 2 ##STR10## where R¹⁰ can representthe groups (C₁ -C₆)alkyl, where the alkyl group can be straight-chainedor branched, (C₃ -C₇)cycloalkyl, and phenyl which can be substitutedwith alkyl, alkoxy, halogen, the benzylhydryl and the bis-F-benzylhydrylgroup, furthermore

R⁵ can represent a 2-, or 4-pyrimidinylamino ring, which can besubstituted several times with a methyl group or a 4-piperidylaminoring, where the N-atom of the piperidine ring can be substituted in eachcase with H, (C₁ -C₆)alkyl, where the alkyl group can bestraight-chained or branched, (C₃ -C₇)cycloalkyl, aralkyl, phenyl or thepyridine ring substituted with the groups NH₂, NO₂, OCH₃ and NHCOOEt,

R⁵ also represents the 3- or 4-tetrahydropyridylamino ring, the N-atomof which can be substituted by H, (C₁ -C₆)alkyl, where the alkyl groupcan be straight-chained or branched, (C₃ -C₇)cycloalkyl and aralkyl,

Z can represent O or S or two hydrogen atoms

for G=(ii)

R¹¹ can have the same meaning as R¹,

R¹² and R¹³ can be the same or different and independently of oneanother occupy all the carbon positions at the (non-aromatic)heterocyclic system and have the meaning given above for R¹ and

o can be 1-4

for G=(iii)

R¹⁴ can represent benzyl that can be substituted once or several timesby halogen, (C₁ -C₆)-alkyl, where the alkyl group can bestraight-chained or branched, (C₁ -C₆)alkoxy or benzyloxy, or the group##STR11## where R¹⁵ can be hydroxy, 2,3- or 4-pyridylamino, that can besubstituted with an amino, nitro (C₁ -C₄)alkoxycarbonyl or (C₁-C₄)alkoxy-carbonylamino, 4-quinolylamino, that can be substituted with(C₁ -C₄)alkyl or 2-pyridylmethoxy.

The compounds of the invention can also be present as acid additionsalts, for example as salts of mineral acids such as hydrochloric acid,sulfuric acid, phosphoric acid, salts of organic acids, such as aceticacid, lactic acid, malonic acid, maleic acid, fumaric acid, glucuronicacid, citric acid, gluconic acid, embonic acid, methan-sulfonicacid,trifluoracetic acid.

The designation "straight-chained alkyl group" is understood to mean forexample radicals such as methyl, ethyl, n-propyl, n-butyl, n-pentyl,n-hexyl, "branched alkyl group" is understood to mean radicals such asisopropyl or tert.-butyl. The designation "alkyl groups" is understoodto mean both "straight-chained" and also "branched" alkyl groups."Cycloalkyl" is understood to mean radicals such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The designationhalogen stands for fluorine, chlorine, bromide or iodine. Thedesignation "alkoxy group" constitutes radicals such as methoxy, ethoxy,propoxy, butoxy, isoproloxy, isobutoxy or pentoxy.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the invention display a good effect in pharmacologicalmodels for the release of histamine according to the followinginstructions:

Inhibition of allergically-induced histamine release in-vitro (CHIR)

The method described herein below was carried out after Jasani &Stanworth, 1979, J. Immunol. Meth. 30, 55. Sprague-Dawley rats weresensitised against egg albumin (EA) by subcutaneous injection of 30 mgEA with killed Bordetella pertussis bacteria as adjuvant. Four weekslater, the mast cells of the peritoneal and pleura cavities wereisolated from these animals. The cells were washed, resuspended in trisgel CM (the composition of tris gel CM buffer is as follows:

    ______________________________________                                        tris              25 mMol/l                                                     NaCl 120 mMol/l                                                               CaCl.sub.2  0.5 mMol/l                                                        gelatin 0.01% (% by weight)                                                 ______________________________________                                    

the rest is water, the pH value of the solution is 7.6) buffer andpre-incubated with the test substances for 15 minutes at 37° C. Thecells were then stimulated at 37° C. by adding the antigen EA to releasehistamine. After 30 minutes the cells were centrifuged off and thehistamine released was determined in the cell supernatant using afluorometric method (Shore et al. 1959, J. Pharmacol. Exp. Ther. 127,182).

The compounds also displayed effects in inhibiting the anti-CD3-inducedrelease of interleucin-4 and interleucin-5 according to the followinginstructions:

Inhibition of anti-CD3-induced release of interleucin (IL)-4 (CIL4TC)and IL-5-release (CIL5TC) in vitro

The method described hereinbelow was carried out after Munoz et al.1990, J. Immunol. 144, 964. Murine T-helper cells (D10.G4) were used asIL-4/IL-5-producing cells. These cells were pre-incubated with the testsubstances for 30 minutes at 37° C. The cells were then stimulated at37° C. to produce interleucins by adding a monoclonal antibody againstthe T-cell receptor domain CD3 (anti-CD3). After 16 hours, the cellswere centrifuged off and the released interleucins were quantified inthe cell supernatant with ELISAs for murine IL-4 and IL-5.

    ______________________________________                                        Table of pharmacological experimental results                                   Compound  CHIR [μmol/l]                                                                          CIL4TC [μmol/l]                                                                      CIL5TC [nmol/l]                             ______________________________________                                        D-22558 IC50-0.016  IC50-7967   IC50-1521                                       D-22559 IC50-3.4 51% with IC50-6601                                             10 000 nmol/l                                                               D-22561 15% with 10 IC50-5683 IC50-3214                                       D-22685 33% with 10 IC50-8577 IC50-6887                                       D-22686 IC50-0.20 41% with IC50-7314                                            10 000 nmol/l                                                               D-22693 IC50-0.4 48% with IC50-2702                                             10 000 nmol/l                                                               D-22697 --,-- IC50-7287 IC50-2881                                             D-22698 --,-- 38% with IC50-7765                                                10 000 nmol/l                                                               D-22992 IC50-0.68 IC50-9734 IC50-6237                                         D-22993 IC50-0.54 IC50-8973 IC50-6935                                       ______________________________________                                         CHIR = Inhibition of allergicallyinduced histamine release in vitro effec     Concentration unit: 10,000 nmol/l                                             Effect: % inhibition                                                     

The in vitro investigations with D-22557 and D-22558 were continued invivo (late phase eosinophilia model) in sensitised guinea pigs

Method:

Male guinea pigs (Pirbright White, 200-250 g. Charles River Wiga,Sulfeld) were actively sensitised using a s.c. injection cf ovalbumin(10μg+100 mg aluminium hydroxide) and boosted 2 weeks later. One weekafter the booster injection the animals were exposed for 30 seconds toan aerosol made from 0.5% ovalbumin solution. 24 hours laterbrochoalveolar lavage (BAL) was carried out with 2×5 ml physiol. saltsolution in animals sacrificed using an overdose of pentobarbital sodiumand desanguinated. The lavage fluid was pooled, centrifuged for 10minutes at 400×g and the cell pellet resuspended in 1 ml physiologicalsalt solution. The eosinophiles were counted in a Neubauer chamber afterstaining by using a Becton Dickinson eosinophile test kit. PercentageInhibition of the eosinophilia in the lavage was calculated in percentby comparing the eosinophile count of the groups treated with substancewith the eosinolphile count of normal (unchallenged) and challengedcontrol groups not treated with the substance. Each group numbered 10animals. Test substances were either given prophylactically 2 hoursbefore allergen challenge (-2 h) or therapeutically 4 hours afterchallenge (+4 h). When the therapeutic application was investigated, theanimals (all groups) received azelastin (10 μg/kg po) 2 hours beforeallergen challenge to avoid deaths arising due to the onset of earlyphase bronchoconstriction.

Results:

    ______________________________________                                                  Dose (mg/kg) +                                                                             Time of                                                  Substance Route treatment % Inhibition                                      ______________________________________                                        D-22557   0.5 ip       -2 h     59%                                              1 ip -2 h 42%                                                                 5 ip -2 h 50%                                                                D-22558 5 ip -2 h 41%                                                         D-22558 10 po -2 h 23%                                                         30 po -2 h 35%                                                               D-22558 10 ip +4 h 59%                                                      ______________________________________                                    

The processes for preparing the compounds of the invention are describedby way of example in the following reaction diagrams I-VI and in generalinstructions. All the compounds can be prepared as described or byanalogous means.

The compounds of general formula 1 with G=(i)

W=CH

X=CH

Y=single bond, such that the heterocyclic ring system is directlyassociated with the group ##STR12## Z=O may be obtained according to thefollowing diagram:

DIAGRAM 1 ##STR13##

In accordance with the above diagram I, the 4-aminopyridine compound wasobtained as well as the 3-aminopyridine compound.

N-(4-pyridyl)-[1-(4-fluorobenzyl)indole-3-yl]acetamide (D-22558)

Variant 1 for the Preparation of the CompoundN-(4-Pyridyl)-[1-(4-fluorobenzyl)indole-3-yl]acetamide

1st step

[1-(4-fluorobenzyl)indole-3-yl]acetic acid-(4-fluorobenzyl)ester

100 ml dimethylsulfoxide (DMSO) are added to a three-necked flask underan N₂ atmosphere, 2.1 g sodium hydride (mineral oil suspension) areadded with vigorous stirring and treated dropwise with a solution of 5 g(17.8 mmol) indole-3-acetic acid in 50 ml DMSO. 2.58 g (35.6 mMol)4-fluorobenzyl chloride are added with further stirring. After 12 hoursat 25° C. the reaction mixture is added to 300 ml water and extractedwith ether. The organic phase is dried and the solvent is removed underreduced pressure. The residue is purified by column chromatography onsilica gel.

Eluting mixture: methylene chloride/petroleum ether (80:20). Yield: 78%of theory.

2nd step

[1-(4-fluorobenzyl)indole-3-yl]acetic acid

8.7 g (22.2 mMol) [1-(4-fluorobenzyl)indole-3-yl]acetic acid(4-fluorobenzyl)ester are dissolved in 50 ml ethanol. 110 ml 1N sodiumhydroxide solution are added and the mixture heated for 1 hour atreflux. After cooling, the aqueous phase is washed with ether,acidulated with concentrated hydrochloric acid and the precipitatefiltered.

Yield: 6 g

3rd step

Preparation of the compoundN-(4-pyridyl)-[1-(4-fluorobenzyl)indole-3-yl]acetamide (D-22558)

3.5 g (12.3 mMol) [1-(4-fluorobenzyl)indole-3-yl]acetic acid aredissolved in 100 ml anhydrous tetrahydrofuran. To this solution areadded 2.54 g (12.3 mMol) dicyclohexylcarbodiimide and 1.16 g (12.3 mMol)4-aminopyridine. After stirring for 24 hours at 0° C., the formeddicyclohexyl urea is separated off. After mixing in the solvent, theresidue is purified by column chromatography on silica gel. Elutingagent:

methylene chloride/ethanol: 95:5 (V/V). Yield: 65% of theory; Meltingpoint: 55-60° C.

Elementary analysis:

    ______________________________________                                        calc.   C 73.52        H 5.05  N 11.69                                          found C 73.18 H 4.95 N 11.45                                                ______________________________________                                    

General Instructions for the Preparation of the Compounds of GeneralFormula 1 According to Diagram I

1st step:

The indole carboxylic acid derivative is added to a protic, dipolaraprotic or unpolar organic solvent such as isopropanol, THF, DMSO, DMA,dioxan, toluene, DMF, N-methylpyrrolidone or methylene chloride andadded dropwise under N₂ atmosphere to a double molar suspension of abase prepared in a three-necked flask, such as sodium hydride,pulverised KOH, tert. BuOK, dimethylaminopyridine or sodium amide(mineral oil suspension) in a suitable solvent. The desiredalkylaralkyl-, heteroaralkyl or aryl halide is added to the mixture,optionally in addition of a catalyst, such as Cu, and under stirring,for example in a range of 30 minutes to 3 hours, the temperature beingmaintained within a range from 0° C. to 120° C., preferably 30° C. to80° C., particularly at 50° C.-60° C. When the reaction is completed,the reaction mixture is added to water, extracted for example withdiethyl ether dichloromethane, methyl-tert.-butyl ether ortetrahydrofuran and the collected organic phase is dried with anhydroussodium sulfate. The solvent is removed under reduced pressure, theresidue crystallised by milling, or the oily residue is purified byrecrystallisation, by column chromatography or by flash chromatographyon silica gel or aluminium oxide. The eluting mixture is for exampledichloromethane and diethylether in a ratio of 8:2 (Vol/Vol) or amixture of dichloromethane and ethanol in a ratio of 9:1 (Vol/Vol).

2nd step:

The N-substituted indole carboxylic acid ester obtained according to theabove instructions (1st step) is dissolved in ethanol and treated with1N sodium hydroxide solution. The saponification reaction is carried outbetween 20° C. and 100° C., preferably between 40° C. and 80° C.,particularly between 50° C. and 60° C. After 1-2 hours the mixture iscooled to room temperature, acidulated with hydrochloric acid orconcentrated hydrochloric acid and the precipitated N-substituted indoleacetic acid is isolated by filtration.

3rd step:

The acid obtained according to the above instructions (2nd step) isdissolved in anhydrous tetrahydrofuran. Dicyclohexyl carbodiimide isadded as condensation agent followed by the substituted primary orsecondary amine. After stirring for 24 hours at a temperature of 0°C.-50° C., preferably from 0° C.-30° C., particularly between 0° C. and-200° C., the formed urea is filtered. After evaporation of the solvent,the residue is recrystallised or purified chromatographically oversilica gel. The eluting solvent used is, for example, a mixture ofdichloromethane and ethanol (95:5 Vol/Vol).

Instead of dicyclohexylcarbodiimide (DCC) as condensation agent in thecondensation reaction in step 3 it is also possible to usediisopropylcarbodiimide (DIC) as condensation agent.

The condensation reaction of step 3 can, however, also be carried outusing triphenylphosphine and bromotrichloromethane in THF at atemperature of 30° C.-70° C. instead of using DCC/THF or DIC/THF.Furthermore, the combinations carbonyldiimidazole in anhydrous THF wereused for the condensation reaction (step 3) at a temperature of 0° C. to60° C., preferably at a temperature of 10° C.-30° C., particularly at25° C. As an additional condensation agent used in the condensationreaction in step 3, the combination 1-methyl-2-chloropyridinium iodidewith triethylamine was used in dichloromethane at a temperature of 0°C.-80° C., preferably between 30° C. and 70° C., particularly between50° C. and 60° C.

According to these general instructions for steps 1-3, the followingcompounds were synthesised and are listed in the following summary,quoting their code numbers (D-number) and the corresponding chemicaldesignation. The following table 1 shows, the structures of thesecompounds, their melting points and R_(F) values as well as the couplingreagents used for their preparation in the condensation reaction (step3) from the general formula 1 and the substituents Y-G, X, R¹, R², R³and W:

A: dicyclohexylcarbodiimide or diisopropylcarbodiimide solvent:anhydroustetrahydrofuran (DCC(DIC)/THF)

B: triphenylphosphine/bromotrichloromethane (Ph₃ P/BrCCl₃ /THF)

C: carbonyldiimidazole/TMF(CDI)THF)

D: 1-methyl-2-chloropyridinium iodide/triethylamine in the solventmethylene chloride

    ______________________________________                                        D-22553 N-(3-pyridyl-yl)-(1-methylindole-3-yl)acetamide                         D-22560 N-(4-pyridyl-yl)-(1-benzylindole-3-yl)acetamide                       D-22680 N-(3-pyridyl-yl)-(1-benzylindole-3-yl)acetamide                       D-22681 N-(3-pyridyl-yl)-1-[(4-fluorobenzylindole-3-                           yl]propionamide                                                              D-22684 N-(3-pyridyl-yl)-3-(1-methylindole-3-                                  yl]propionamide                                                              D-23198 1-(3-(1-(4-fluorobenzyl)indole-3-yl)propionamide)-                     4-(4-chlorophenyl)piperazine                                                 D-23245 N-(4-pyridyl-yl)-4-(1-(4-fluorobenzyl)indole-3-                        yl)butyramide                                                                D-23496 N-(2,6-dimethylpyridine-2-yl)-2-[1-(4-fluoro-                          benzyl)indole-3-yl]acetamide                                                 D-22682 N-(3-pyridyl-yl)-3-(1-benzylindole-3-                                  yl)propionamide                                                              D-22683 N-(4-pyridyl-yl)-3-(1-benzylindole-3-                                  yl)propionamide                                                              D-22689 N-(4-pyridyl-yl)-3-(1-methylindole-3-                                  yl)propionamide                                                              D-22690 N-(4-pyridyl-yl)-3-[1-(4-fluorobenzyl)indole-3-                        yl]propionamide                                                              D-22691 N-(4,6-dimethylpyridine-2-yl)-3-[1-(4-fluoro-                          benzyl)indole-3-yl]propionamide                                              D-22693 N-(4-pyridyl-yl)-2-(1-ethylindole-3-yl)acetamide                      D-22694 N-(4,6-dimethylpyridine-2-yl)-2-(1-ethylindole-3-                      yl)acetamide                                                                 D-22695 N-(4,6-dimethylpyridine-2-yl)-2-(1-benzylindole-3-                     yl)acetamide                                                                 D-23489 N-(3-pyridyl)-4-(1-benzylindole-3-yl)butyramide                       D-23490 N-(4-pyridyl)-4-(1-benzylindole-3-yl)butyramide                       D-23495 N-(3-pyridyl)-2-[1-(4-fluorobenzyl)indole-3-                           yl]acetamide                                                                 D-23705 N-(2-pyridyl)-3-(1-benzylindole-3-                                     yl)propionamide                                                              D-23725 N-(2-pyridyl)-2-(1-benzylindole-3-yl)acetamide                        D-23728 N-(2-pyridyl)-3-[1-(4-fluorobenzyl)indole-3-                           yl]propionamide                                                              D-22552 N-(4-pyridyl)-4-(indole-3-yl)butyramide                               D-22701 N-(4,6-dimethylpyridine-2-yl)-3-(benzylindole-3-                       yl)propenamide                                                               D-23200 (N-(4,6-dimethylpyridine-2-yl)-3-[1-(4-                                fluorobenzyl)indole-3-yl]propionamide                                        D-22940 1-[2-(indole-3-yl)acetamide]-4-(4-chlorophenyl)                        piperazine                                                                   D-22941 1-[2-(indole-3-yl)acetamide]-4-(4,4'-                                  bisfluorobenzhydryl)piperazine                                               D-22943 1-[2-(indole-3-yl)acetamide]-4-methylpiperazine                       D-23197 1-[3-(indole-3-yl)propionamide]-4-(4,4'-bisfluoro-                     benzhydryl)piperazine                                                        D-23247 N-(4-pyridyl)-3-(1-benzyl-5-methoxyindole-3-                           yl)propionamide                                                              D-23246 N-(4-pyridyl)-3-[1-(4-fluorobenzyl)-5-                                 fluoroindole-3-yl]propionamide                                               D-23244 N-(4-pyridyl)-3-(1-benzyl-5-fluoroindole-3-                            yl]propionamide                                                              D-22946 1-[3-(indole-3-yl)propionamide]-4-(4-chlorophenyl)-                    piperazine                                                                   D-22945 1-[3-(indole-3-yl)propionamide]-4-(4-methoxy-                          phenyl)piperazine                                                            D-22944 1-[3-(indole-3-yl)propionamide]-4-methylpiperazine                    D-22942 1-[2-(indole-3-yl)acetamide]-4-(4-methoxyphenyl)                       piperazine                                                                   D-23243 N-(4-pyridyl)-3-(1-benzylindole-3-yl)acrylamide                       D-23242 N-(4-pyridyl)-3-(5-chloroindole-3-                                     yl)propionamide                                                              D-23241 N-(4-pyridyl)-3-(5-chloroindole-3-                                     yl)propionamide                                                              D-23240 N-(4-pyridyl)-3-(5-methoxyindole-3-yl)propion-                         amide                                                                        D-23239 N-(4-pyridyl)-3-[1-(4-fluorobenzyl)-5-iso-                             propyl-indole-3-yl]propionamide                                              D-23238 N-(4-pyridyl)-3-(5-isopropylindole-3-                                  yl)propionamide                                                              D-23488 N-(4-pyridyl)-2-(5-chloroindole-3-yl)acetamide                        D-23491 N-(4-pyridyl)-2-[1-(4-fluorobenzyl)-2-methyl-5-                        isopropylindole-3-yl]acetamide                                               D-23492 N-(4-pyridyl)-2-(1-benzyl-5-fluoroindole-3-yl)                         acetamide                                                                    D-23493 N-(4-pyridyl)-2-[1-(4-fluorobenzyl)-5-                                 chloroindole-3-yl]acetamide                                                  D-23494 N-(4-pyridyl)-2-[1-(4-fluorobenzyl)-5-                                 fluoroindole-3-yl]acetamide                                                  D-23497 N-(4-pyridyl)-2-(2-methyl-5-isopropylindole-3-                         yl)acetamide                                                                 D-23498 N-(4-pyridyl)-3-[1-(4-fluorobenzyl)-5-                                 methoxyindole-3-yl]propionamide                                              D-23499 N-(4-pyridyl)-2-(2-methyl-5-chloroindole-3-yl)-                        acetamide                                                                    D-23500 N-(4-pyridyl)-3-(1-benzyl-5-isopropylindole-3-                         yl)propionamide                                                              D-23501 N-(4-pyridyl)-2-(1-benzyl-2-methyl-5-fluoro-                           indole-3-yl)acetamide                                                        D-23502 N-(4-pyridyl)-2-(2-methyl-5-methoxyindole-3-                           yl)-acetamide                                                                D-23703 N-(4-pyridyl)-2-(5-methoxy-1H-indole-3-yl)-                            acetamide                                                                    D-23721 N-(4-pyridyl)-3-[5-chloro-1-(4-fluorobenzyl)-                          indole-3-yl]propionamide                                                     D-23735 N-(4-pyridyl)-2-(1-benzyl-5-chloroindole-3-                            yl)acetamide                                                                 D-23727 N-(4-pyridyl)-2-[1-(4-fluorobenzyl)-5-                                 isopropyl-indole-3-yl]acetamide                                              D-23707 N-(4-pyridyl)-2-(5-fluoro-2-methylindole-3-                            yl]acetamide                                                                 D-223712 N-(4-pyridyl)-2-(1-(4-fluorobenzyl)-2-methyl-5-                       fluoroindole-3-yl]acetamide                                                  D-23708 N-(4-pyridyl)-2-(1-benzyl-2-methyl-5-                                  isopropylindole-3-yl]acetamide                                               D-23729 N-(4-pyridyl)-3-(1-benzyl-5-chloroindole-3-                            yl)propionamide                                                              D-23702 N-(4-pyridyl-yl)-2-[1-(4-fluorobenzyl)-2-methyl-5-                     methoxyindole-3-yl]acetamide                                                 D-23718 N-(4-pyridyl-yl)-2-[1-(4-fluorobenzyl)-2-methyl-5-                     chloroindole-3-yl]acetamide                                                  D-23722 N-(4-pyridyl-yl)-3-[1-(4-fluorobenzyl)indole-3-                        yl]acrylamide                                                                D-23724 N-(4-pyridyl-yl)-2-(1-benzyl-5-isopropylindole-3-                      yl]acetamide                                                                 D-23701 N-(2-pyridyl-yl)-2-[1-(4-fluorobenzyl)indole-3-                        yl]acetamide                                                                 D-23711 N-(4-pyridyl-yl)-2-(5-isopropyl-1H-indole-3-                           yl]acetamide                                                                 D-23726 N-(4-pyridyl-yl)-2-(5-fluoro-1H-indole-3-                              yl]acetamide                                                                 D-23698 N-(4-pyridyl-yl)-2-[1-benzyl-5-methoxyindole-3-                        yl]acetamide                                                                 D-23700 (E)-N-(4,6-dimethylpyridine-2-yl)-3-(1-methyl-                         indole-3-yl)acrylamide                                                       D-23719 N-(4-pyridyl-yl)-2-[1-(4-fluorobenzyl)-5-                              fluoro(indole-3-yl)]acetamide                                                D-23732 N-[2,6-dimethyl-(4-pyrimidyl]-2-[1-(4-                                 fluorophenyl)-5-fluoro(indole-3-yl]acetamide                                 D-23717 N-(4-pyridyl-yl)-2-[1-(4-fluorophenyl)-indole-3-                       yl]acetamide                                                                 D-23733 N-[2,6-dimethyl-(4-pyrimidyl]-2-[1-(4-                                 fluorophenyl)-indole-3-yl]acetamide                                          D-23734 N-(4-pyridyl-yl)-2-[1-(4-fluorophenyl)-5-methoxy-                      indole-3-yl)acetamide                                                        D-23730 N-(4-pyridyl)-3-[(5-benzyloxy-1H-(indole-3-                            yl]propionamide                                                              D-23720 N-(4-pyridyl)-2-[1-(4-fluorophenyl)-6-methoxy-                         indole-3-yl]acetamide                                                        D-24034 N-(4-pyridyl)-2-[(1-n-butyl-(indole-3-                                 yl))acetamide                                                                D-24035 N-(4-pyridyl)-2-[1-(4-chlorobenzyl)-(indole-3-                         yl)]acetamide                                                                D-24036 N-(4-pyridyl)-2-[1-(3-fluorobenzyl)-indole-3-                          yl]acetamide                                                                 D-24040 N-(4-pyridyl)-2-[1-(2-fluorobenzyl)-indole-3-                          yl)acetamide                                                                 D-24041 N-(4-pyridyl)-2-[1-(3-trifluoromethylbenzyl)-                          indole-3-yl]acetamide                                                        D-24042 N-(2-pyridyl)-ethyl)-2-[1-(4-fluoro-                                   benzyl)indole-3-yl]acetamide                                                 D-24236 N-[(2-pyridyl)-methyl]-{1-(4-fluorobenzyl)-                            indole-3-yl]acetamide                                                        D-24244 N-[4-(4-pyridyl)-methyl)phenyl]-2-[1-(4-                               fluorobenzyl)indole-3-yl]acetamide                                           D-24238 N-[(3-pyridyl)-methyl]-[1-(4-fluoro-                                   benzyl)indole-3-yl]acetamide                                                 D-24239 N-[(4-pyridyl)-methyl]-[1-(4-fluoro-                                   benzyl)indole-3-yl]acetamide                                                 D-23714 N-(4-pyridyl)-2-[1-(4-fluorobenzyl)-6-                                 hydroxyindole-3-yl]acetamide                                               ______________________________________                                    

    TABLE 1       - New indole derivatives according to reaction diagram 1      ##STR14##     1     D  X R.sup.1 R.sup.2 R.sup.3 W Fp[°      C.] CR        Y--G       22553      ##STR15##     2  CH CH.sub.3 H H CH 152 A     22560      ##STR16##     3  CH      ##STR17##     4  H H CH 40-60 (deliquesce) A     22680      ##STR18##     2  CH      ##STR19##     4  H H CH 160 A     22681      ##STR20##     5  CH      ##STR21##     6  H H CH 116 A     22684      ##STR22##     5  CH CH.sub.3 H H CH 129 A     23198      ##STR23##     7  CH      ##STR24##     6  H H CH oil D     23245      ##STR25##     8  CH      ##STR26##     6  H H CH oil D     23496      ##STR27##     9  CH      ##STR28##     6  H H CH 132 D     22682      ##STR29##     0  CH      ##STR30##     4  H H CH 120 A     22683      ##STR31##     1  CH      ##STR32##     6  H H CH 154 A     22689      ##STR33##     1  CH CH.sub.3 H H CH 118 A     22690      ##STR34##     1  CH      ##STR35##     6  H H CH 125 A     22691      ##STR36##     2  CH      ##STR37##     6  H H CH 40-60 (deliquesce) B     22693      ##STR38##     3  CH CH.sub.2      CH.sub.3 H H CH 130-132 A                   22694      ##STR39##     9  CH CH.sub.2      CH.sub.3 H H CH 159 B                   22695      ##STR40##     9  CH      ##STR41##     4  H H CH 40-60 (deliquesce) B     23489      ##STR42##     3  CH      ##STR43##     4  H H CH 110 D     23490      ##STR44##     8  CH      ##STR45##     4  H H CH      93 D              23495      ##STR46##     2  CH      ##STR47##     6  H H CH 145 D     23705      ##STR48##     2  CH      ##STR49##     4  H H CH 116-118 D     23725      ##STR50##     2  CH      ##STR51##     4  H H CH 118-120 D     23728      ##STR52##     2  CH      ##STR53##     6  H H CH 104-105 D     22552      ##STR54##     8  CH H H H CH      91 A                     R Y--G       22701      ##STR55##     4  CH      ##STR56##     4  H H CH 174 B     23200      ##STR57##     4  CH      ##STR58##     6  H H CH oil B     22940      ##STR59##     5  CH H H H CH 236-238 C     22941      ##STR60##     6  CH H H H CH 162-164 C     22943      ##STR61##     7  CH H H H CH 152-154 C     23197      ##STR62##     8  CH H H H CH 190-192 D     Y --G       23247      ##STR63##     1  CH      ##STR64##     4  5-OCH.sub.3 H CH 60-70 (deliquesce) D     23246      ##STR65##     1  CH      ##STR66##     6  5-F H CH 60-70 (deliquesce) D     23244      ##STR67##     1  CH      ##STR68##     4  5-F H CH 185 D     22946      ##STR69##     9  CH H H H CH 189-191 C     22945      ##STR70##     0  CH H H H CH 170-172 C     22944      ##STR71##     1  CH H H H CH 154-156 C     22942      ##STR72##     2  CH H H H CH 174-176 C     23243      ##STR73##     3  CH      ##STR74##     4  H H CH 239-240 D     23242      ##STR75##     1  CH H 5-Cl H CH 189 D     23241      ##STR76##     1  CH H 5-F H CH 150-160 D     23240      ##STR77##     1  CH H 5-OCH.sub.3 H CH 142 D     23239      ##STR78##     1  CH      ##STR79##     6      ##STR80##     4  H CH 45-55 (deliquesce) D     23238      ##STR81##     1  CH H      ##STR82##     4  H CH 70-78 (deliquesce) D     23488      ##STR83##     3  CH H 5-Cl H CH 200 (disint.) D     23491      ##STR84##     3  CH.sub.3      ##STR85##     6      ##STR86##     4  H CH 174 D     23493      ##STR87##     3  CH.sub.3      ##STR88##     6  5-Cl H CH 150-156 D     23494      ##STR89##     3  CH      ##STR90##     6  5-F H CH 70-76 (deliquesce) D     23497      ##STR91##     3  C--CH.sub.3 H      ##STR92##     4  H CH 209 D     23492      ##STR93##     3  CH      ##STR94##     4  5-F H CH 130-137 D     23498      ##STR95##     1  CH      ##STR96##     4  5-OCH.sub.3 H CH 144 D     23499      ##STR97##     3  C--CH.sub.3 H 5-Cl H CH >250 D     23500      ##STR98##     1  CH      ##STR99##     4      ##STR100##     4  H CH 50 (deliquesce) D     23501      ##STR101##     3  C--CH.sub.3      ##STR102##     4  5-F H CH 85-90 D     23502      ##STR103##     3  C--CH.sub.3 H 5-OCH.sub.3 H CH 203 D     23703      ##STR104##     3  CH H 5-OCH.sub.3 H CH 166-167 D     23721      ##STR105##     1  CH      ##STR106##     6  5-Cl H CH 58-60 (deliquesce) D     23735      ##STR107##     3  CH      ##STR108##     4  5-Cl H CH 138-140 D     23727      ##STR109##     3  CH      ##STR110##     6      ##STR111##     4  H CH 88 D     23707      ##STR112##     3  C--CH.sub.3 H 5-F H CH 200 (disinte.) D     23712      ##STR113##     3  C--CH.sub.3      ##STR114##     6  5-F H CH      95-105 (deliquesce) D                 23708      ##STR115##     3  C--CH.sub.3      ##STR116##     4      ##STR117##     4  H CH 164 D     23729      ##STR118##     1  CH      ##STR119##     4  5-Cl H CH 160 D     23702      ##STR120##     3  C--CH.sub.3      ##STR121##     6  5-OCH.sub.3 H CH 162 D     23718      ##STR122##     3  C--CH.sub.3      ##STR123##     6  5-Cl H CH 145 D     23722      ##STR124##     5  CH      ##STR125##     6  H H CH >250 D     23724      ##STR126##     3  CH      ##STR127##     4      ##STR128##     4  H CH 67-68 D     23701      ##STR129##     6  CH      ##STR130##     6  H H CH 110-111 D     23711      ##STR131##     3  CH H      ##STR132##     4  H CH 174 D     23726      ##STR133##     3  CH H 5-F H CH 200 (disinte.) D     23698      ##STR134##     3  CH      ##STR135##     4  5-OCH.sub.3 H CH 145-146 D     23700      ##STR136##     4  CH CH.sub.3 H H CH 162-163 D     23719      ##STR137##     3  CH      ##STR138##     7  5-F H CH 186 D     23732      ##STR139##     8  CH      ##STR140##     7  5-F H CH 55 (deliquesce) D     23717      ##STR141##     3  CH      ##STR142##     7  H H CH 152 D     23733      ##STR143##     8  CH      ##STR144##     7  H H CH 55 (deliquesce) D     23734      ##STR145##     3  CH      ##STR146##     7  5-OCH.sub.3 H CH 218 D     23730      ##STR147##     1  CH H      ##STR148##     9  H CH 170 D     23720      ##STR149##     3  CH      ##STR150##     7  6-OCH.sub.3 H CH 152 D     24034      ##STR151##     3  CH CH.sub.2 CH.sub.2 CH.sub.2      CH.sub.3 H H CH oil D                                     24035      ##STR152##     3  CH      ##STR153##     0  H H CH 153 D     24036      ##STR154##     3  CH      ##STR155##     1  H H CH 161 D     24040      ##STR156##     3  CH      ##STR157##     5  H H CH 146 D     24041      ##STR158##     3  CH      ##STR159##     2  H H CH 127 D     24042      ##STR160##     3  CH      ##STR161##     6  H H CH      87 D              24236      ##STR162##     4  CH      ##STR163##     6  H H CH      75 D              24244      ##STR164##     5  CH      ##STR165##     6  H H CH 118 D     24238      ##STR166##     6  CH      ##STR167##     6  H H CH 163 D     24239      ##STR168##     7  CH      ##STR169##     6  H H CH 139-140 D     23714      ##STR170##     3  CH      ##STR171##     8  6-OH H CH 213 --     23635      ##STR172##     3  CH      ##STR173##     9  H H CH 79 (disint.) D     23644      ##STR174##     0  CH      ##STR175##     9  H H CH 54 (disint.) D     23681      ##STR176##     1  CH      ##STR177##     9  H H CH 156-161 D     23767      ##STR178##     2  CH      ##STR179##     9  H H CH 118-120 D     23784      ##STR180##     2  CH      ##STR181##     2  H H CH 144-145 D     23785      ##STR182##     0  CH      ##STR183##     2  H H CH 111-112 D     23841      ##STR184##     3  CH      ##STR185##     2  H H CH 181-183 (oxalate) D

Starting compounds for the compounds of general formula 1, preparedaccording to synthesis diagram I, which emerge from table 1(intermediate syntheses):

Final synthesis steps

(D-compounds) of general formula 1 from table I and their primary steps

A) 22558, 22560, 22680, 22693, 22694, 22695, 22940, 22941, 22943, 22942,22944, 22945, 23495, 23496, 23699 23701, 23725, 23635, 23644, 23681,22553, 23767

(N-alkylation agent: CH₃) instead of 4-fluorobenzylchloride in diagram1)

from (indole-3-yl)acetic acid (commercially available);

B) 24035, 24040, 24041, 24042, 24236, 24244, 24238, 24239, 23784, 23785,23841

from (indole-3-yl)acetic acid ethyl ester (commercially available);

C) 22681, 22682, 22683, 22684, 22689, 22690, 22691, 22946, 23197, 23198,23728, 23705,

from (indole-3-yl)acetic acid ethyl ester (commercially available);

D) 22552, 23245, 23489, 23490

from (indole-3-yl)butyric acid (commercially available);

E) 23492, 23494, 23726

from (5-fluoro-indole-3-yl)acetic acid (commercially available);

Continuation of the intermediate syntheses for the compounds of thegeneral formula of table 1

F) 23703, 23698

from (5-methoxyindole-3-yl)acetic acid (commercially available);

G) 23238, 23239, 23240, 23241, 23242, 23244, 23246, 23247, 23498, 23500,23730

The C-5-substituted (indole-3-yl)propionic acids are synthesised byanalogy with the following literature reference:

L. Kalb, F. Schweizer, Chem. Ber. 59, 1860 (1926)

H) 23488, 23491, 23493, 23497, 23499, 23501, 23502, 23721, 23735, 23427,23707, 23712, 23708, 23729, 23702, 23718, 23724, 23727, 23711, 23720

The C-2-, C-5- and C-6-substituted indole-3-yl acetic acid derivativesthat were needed as primary steps were synthesised according to thefollowing literature instructions:

a) S. Findlay and G. Dougherty,

J. Org. Chem. 13, 560 (1948)

b) H. Yao and P. Resnick, J. Amer. Chem. 84, 3514 (1962)

c) H. Plieninger, Chem.Ber. 87. 228 (1954)

d) Houben-Weyl E6bl "Hetarene I--Part 2a", p. 716-720, Georg ThiemePublishers, Stuttgart--New York (1994)

Continuation of the intermediate syntheses for the compounds of table 1

I) 23243, 23722, 22701

(N-benzyl-3-yl)acrylic acid or N-[4-(fluorobenzyl)indole-3-yl]acrylicacid were prepared according to the synthesis path described hereinbelowand the corresponding synthesis instructions:

Synthesis instructions:

1-benzyl-(indole-3-yl)carboxaldehyde

To a solution of 10 g (68.9 mMol) indole-3-carboxaldehyde in 50 mldioxan are added 13.5 g K₂ CO₃ and 9 ml (75 mMol) benzylbromide. Afterstirring 12 hours at room temperature 200 ml water are added and themixture is extracted with methylene chloride. The organic phase iswashed with water, dried with sodium sulfate and concentrated in vacuum.After purification by column chromatography (eluting solvent:dichloromethane), 14.2 g of the desired compound are obtained. Yield:88% of theory

(1-benzylindole-3-yl)acrylic acid methylester

8 g (34 mMol) 1-benzyl(indole-3-yl)carboxaldehyde and 25 g (74.8 mMol)triphenylphosphoranylide acetic acid methyl ester in 200 ml dioxan arerefluxed for 48 hours. The dioxan is evaporated and under reducedpressure the residue is purified by column chromatography in silica gelwith a mixture of dichloromethane/hexane 80:20. 8.9 g of yellow crystalsare obtained.

Yield: 90% of theory. (

1-benzylindole-3-yl)acrylic acid

43 ml (87 mMol) sodium hydroxide solution are added to a solution of 8.5g (29,2 mMol) of the above ester in 50 ml ethanol. The mixture isrefluxed for 1 hour. After cooling, 200 ml water are added, and themixture is acidulated with conc. HCl. The (1-benzylindole-3-yl)acrylicacid precipitates in the form of white crystals. Yield: 88% of theory

Continuation of the intermediate syntheses for the compounds of table 1

K) 23719, 23732, 23717, 23733, 23734

The final products were prepared from[N-(4-fluorophenyl)-5-fluoro-(indole-3-yl)acetic acids according to thefollowing synthesis scheme and the following syntheses instructions:

Synthesis of the intermediate of compound D 23719: ##STR186##

[N-(⁴ -fluorophenyl)-5-fluoro-(indole-3-yl)]acetic acid ethyl ester

A mixture of 3.9 g (17.6 mMol) [5-fluoro-1H-(indole-3-yl)]acetic acidethyl ester, 4.04 ml (35 mMol) 4-iodide-fluorobenzene, 17.6 potassiumcarbonate, 9.6 g copper powder and 73 ml bromobenzene are refluxed for48 hours. The mixture is then filtered, the solvent removed underreduced pressure and the residue purified by column chromatography onsilica gel with mixtures of dichloromethane/petroleum ether (4:1, v/v)to give 4.4 g of the compound as beige crystals.

Yield: 79% of theory.

[N-(4-fluorophenyl)-5-fluoro-(indole-3-yl)]acetic acid ethyl ester

4.4 g (14 mMol) [N-(4-fluorophenyl)-5-fluoro-(indole-3-yl)]acetic acidethyl ester are dissolved in 39 ml ethanol and mixed with a solution of1.67 g (42 mMol) NaOH in 8 ml water. The mixture is refluxed for 1 hour,the solvent removed under reduced pressure, the residue neutralised with1n hydrochloric acid and then extracted with ethyl acetate. The organicphase is dried with sodium sulfate and the solvent is evaporated underreduced pressure.The residue is crystallized in isopropyl ether asyellow crystals.

Yield: 3.1 g (77% of theory). Melting point: 141° C.

Continuation of the intermediate syntheses for the compounds of table 1

L) 23714

The final product D-23714 is obtained from D-23720 by methylethercleavage with BBr₃ or NaCN in DMSO according to the following literatureinstructions:

a) H. Ulrich et al., J. Org. Chemistry 39, 2437 (1974)

b) J. R. McCarthy et al., Tetrahedron letters 52, 5183 (1978)

c) A. D. Fraser et al., J. Org. Chemistry 41, 170 (1976)

M) 24034

Syntheses of the intermediates of D-24034.

[N-(n-butyl)-(indole-3-yl)]acetic acid ethyl ester

A solution of 0.66 g (27.5 mMol) NaH in 200 ml DMSO is added undernitrogen atmosphere dropwise to a solution of 5.1 g commerciallyavailable (25 mMol) (indole-3-yl)acetic acid ethyl ester in 30 ml DMSOat room temperature. After 30 minutes 3.2 ml (27.6 mMol) n-butyliodideare added. The mixture is stirred for 3 hours, the reaction mixture isdiluted with water and extracted with ether. After drying, the solventis removed under reduced pressure and the residue is purified by columnchromatography on silica gel. Eluting solvent: dichloromethane(petroleum ether (7:2, v/v). 4.4 g of a yellow oil are obtained.

Yield: 68% of theory.

[N-(n-butyl)-indole-3-yl)]acetic acid

The synthesis is carried out according to the saponificationinstructions for the primary step[N-(4-fluorophenyl)-5-fluoro-(indole-3-yl)]acetic acid ethyl ester ofcompound D-23719.

Yield: 96% of theory.

In addition, the compounds of the general formula 1 with G=(i) can beobtained according to the following synthesis Scheme of diagram II,wherein

W=CH

X=CH

Y=a single bond, such that the heterocyclic ring system is associateddirectly with the group ##STR187## Z=2 hydrogen atoms.

DIAGRAM II ##STR188##

According to the above diagram II the compoundN-(pyridine-3-yl)-2-[1-(4-fluorobenzyl)indole-3-yl]ethylamine maleate(D-22557) was obtained.

D-23495 was used as educt. Yield: 83% of theory related to D-23495 used.Elementary analysis:

    ______________________________________                                        C         calc.  67.67       found                                                                              67.62                                         H calc. 5.24 found 5.39                                                       N calc. 9.1 found 8.92                                                      ______________________________________                                    

According to the above diagram II the compoundN-(3-pyridyl)-3-[1-methylindole-3-yl]propylamine maleate (D-22554) wasobtained.

Instructions:

To a solution of 1.2 g (4.3 mMol) of the basic amide D-22684 in 150 mlanhydrous tetrahydrofuran in a three-necked flask are added a suspensionof 0.8 g (21 mmol) LiAlH₄ in 10 ml THF under nitrogen atmosphere andvigorous stirring. The mixture is refluxed for 2 hours and cooled to 15°C. The excess LiAlH₄ is hydrolysed by slow addition of 10 ml iced water.The obtained mixture is extracted several times with methylene chloride,the organic phase is dried with anhydrous sodium sulfate and the solventis removed under reduced pressure. The residue is dried and transferredto the maleate as follows:

Maleate synthesis:

The base of D-22554 obtained as set out above is dissolved in a littleanhydrous ethyl acetate and mixed with a concentrated solution of maleicacid used in equivalent amount to the base in ethyl acetate, the mixtureis left to stand over night at 4° C and the crystalline compoundobtained--D-22554--is filtered.

MP: 118° C.; Yield: 83% of theory related to the maleate. Elementaryanalysis: C calc. 66.13 found 65.92;

    ______________________________________                                        C         calc.  66.13       found                                                                              65.92                                         M calc. 6.08 found 6.21                                                       N calc. 11.02 found 10.94                                                   ______________________________________                                    

General instruction for preparing compounds of general formula 1 byanalogy with diagram II

The indole-3-yl carboxylic acid amide is added in a nitrogen atmosphereto a three-necked flask with stirrer, dropping funnel and reflux coolerinto an anhydrous organic solvent such as diethyl ether, THF, dioxan ortoluene. After adding 2-5 times, preferably 3-times the molar excess ofreducing agent, such as lithium aluminium hydride, sodiumcyanoborohydride or sodium borohydride/activator the mixture is heatedat reflux for 1-2 hours, then cooled to approx. 10° C. and the excessreducing agent hydrolysed with excess water. The reaction mixture isextracted several times with an organic solvent, preferably methylenechloride, chloroform or also ethyl acetate, the combined extracts aredried with anhydrous sodium sulfate and then concentrated to dryness ina vacuum. The base obtained in this manner can be converted to themaleate by the following path.

The base obtained in the above manner is dissolved in an organicsolvent, preferably an alcohol, such as methanol, ethanol or isopropanolor also in an aprotic solvent such as ethyl acetate or methylenechloride and treated with the equivalent amount of maleic acid which isdissolved in a little ethyl acetate or isopropanol. When left at roomtemperature or at 0-5° C., the corresponding maleate crystallises, isfiltered and dried under reduced pressure.

According to this general instruction for the synthesis of new indolederivatives according to diagram II, the following compounds weresynthesised which are listed in the following summary, quoting theircode numbers (D-numbers) and the corresponding chemical designation. Thefollowing table 2 shows the structures of these compounds and theirmelting points from the general formula I and the substituents Y-G, W,X, R¹, R² and R³ :

    ______________________________________                                        D-22551 N-(4-pyridyl-yl)-2-(1-methylindole-3-                                    yl)ethylamine maleate                                                        D-22685 N-(4-pyridyl-yl)-2-(1-benzylindole-3-yl)ethyl                          amine maleate                                                                D-22688 N-(4-pyridyl-yl)-4-(indole-3-yl)butylamine                             oxalate                                                                      D-22696 N-(4-pyridyl-yl)-3-(1-methylindole-3-yl)propyl                         amine maleate                                                                D-22697 N-(4-pyridyl-yl)-3-(1-methylindole-3-yl)propyl                         amine                                                                        D-22554 N-(3-pyridyl-yl)-3-(1-methylindole-3-yl)propyl-                        amine                                                                        D-22555 N-(3-pyridyl-yl)-3-(1-benzylindole-3-yl)propyl                         amine                                                                        D-22557 N-(3-pyridyl-yl)-2-[1-(4-fluorobenzyl)indole-3-                        yl]ethylamine maleate                                                        D-22561 N-(4-pyridyl-yl)-2-[1-(4-fluorobenzyl)indole-3-                        yl]ethylamine maleate                                                        D-23699 N-(2-(4,6-dimethylpyridyl))-2-[1-(4-                                   fluorobenzyl)indole-3-yl]ethylamine maleate                                  D-23704 N-(2-pyridyl-yl)-3-[1-(4-fluorobenzyl)indole-3-                        yl]propylamine                                                               D-23710 N-(3-pyridyl-yl)-2-(1-benzylindole-3-yl)ethyl-                         amine maleate                                                                D-23713 N-(2-pyridyl-yl)-2-[1-(4-fluorobenzyl)indole-3-                        yl]ethylamine                                                                D23723 N-(2-pyridyl-yl)-2-(1-benzylindole-3-yl)-                               ethylamine                                                                   D-24045 N-(4-pyridyl-yl)-2-[1-butyl-indole-3-yl]ethyl-                         amine                                                                        D-24038 N-(4-pyridyl-yl)-2-[1-(4-chlorobenzyl)indole-3-                        yl]ethylamine                                                                D-24043 N-(4-pyridyl-yl)-2-[1-(2-fluorobenzyl)indole-3-                        yl]ethylamine                                                                D-24044 N-(4-pyridyl-yl)-2-[1-(3-trifluoromethyl-                              benzyl)indole-3-yl]ethylamine                                                D-23709 N-(4-pyridyl-yl)-4-[1-(4-fluorobenzyl)indole-3                         yl]butylamine                                                                D-22698 N-(4-pyridyl-yl)-3-[1-(4-fluorobenzyl)indole-3                         yl]propylamine                                                               D-22686 N-(3-pyridyl-yl)-3-3[1-(4-fluorobenzyl)indole-3-                       yl]propylamine                                                               D-23731 N-(4-pyridyl-yl)-4-(1-benzylindole-3-yl)butyl-                         amine                                                                      ______________________________________                                    

                                      TABLE 2                                     __________________________________________________________________________    New indole compounds according to reaction diagram II                         1  STR189##                                                                   D    Y--G            X R.sup.1      W R.sup.2                                                                         R.sup.3                                                                         Fp[° C.]                     __________________________________________________________________________      22551 (Maleat)                                                                                                        3  CH CH.sub.3 CH H H 119                                                       - 22685 (Maleat)                                                            3  CH 191##                                                                   4  CH H H 140                          - 22688 (Oxalat)                                                                                                     4  CH H CH H H  60 (deliquesce)        - 22696 (Maleat)                                                                                                     5  CH CH.sub.3 CH H H 126-128                                                   - 22697                                                                     5  CH 195##                                                                   4  CH H H oil                          - 22554                                                                                                              6  CH CH.sub.3 CH H H 118                                                       - 22555                                                                     6  CH 198##                                                                   4  CH H H  76 (deliquesce)                                                      - 22557 (Maleat)                                                            7  CH 200##                                                                   6  CH H H 142                          - 22561 (Maleat)                                                                                                     8  CH 202##                                                                   6  CH H H 111                          - 23699 (Maleat)                                                                                                     9  CH 204##                                                                   6  CH H H 104-105                      - 23704                                                                                                              0  CH 206##                                                                   6  CH H H 112-113                      - 23710 (Maleat)                                                                                                     7  CH 208##                                                                   4  CH H H 122-124                      - 23713                                                                                                              1  CH 210##                                                                   6  CH H H 110                          - 23723                                                                                                              1  CH 212##                                                                   4  CH H H 116-117                      - 24045                                                                                                              8  CH CH.sub.2 CH.sub.2                                                       CH.sub.2 CH.sub.3 CH H H  51                                                  (deliquesce)                           - 24038                                                                                                              8  CH 215##                                                                   0  CH H H  49 (deliquesce)                                                      - 24043                                                                     8  CH 217##                                                                   2  CH H H 153                          - 24044                                                                                                              8  CH 219##                                                                   3  CH H H oil                          - 23709                                                                                                              4  CH 221##                                                                   6  CH H H 80-90                        - 22698                                                                                                              5  CH 223##                                                                   6  CH H H 126-128                      - 22686 (Maleat)                                                                                                     6  CH 225##                                                                   6  CH H H 136                          - 23731                                                                                                              4  CH 227##                                                                   4  CH H H 60-65 (deliquesce)        __________________________________________________________________________

Starting material for the compounds of general formula 1 which emergefrom table 2 prepared according to synthesis diagram II

Final synthesis products (D-compounds)intermediates of general formula 1from table 2 (correspond to final according to synthesis diagram IIproducts from Tab. 1)

    ______________________________________                                               D-22554                                                                              D-22684                                                           D-22561 D-22558                                                               D-22555 D-22682                                                               D-22557 D-23495                                                               D-22685 D-22560                                                               D-22688 D-22552                                                               D-22696 D-22689                                                               D-22697 D-22683                                                               D-22698 D-22690                                                               D-24038 D-24035                                                               D-24043 D-24040                                                               D-24044 D-24041                                                               D-24045 D-24034                                                               D-23710 D-22680                                                               D-23699 D-23496                                                             ______________________________________                                    

Final synthesis products (D-compounds)intermediates of general formula 1from table 2 (correspond to final according to synthesis diagram IIproducts from Tab. 1)

    ______________________________________                                               D-23713                                                                              D-23701                                                           D-23723 D-23725                                                               D-23709 D-23245                                                               D-23704 D-23728                                                               D-23731 D-23490                                                             ______________________________________                                    

The compounds of general formula 1 with X═ C═, where a single bond ofC=, which is saturated by hydrogen in formula 1 and which is linked viaa methylene group to the N-atom of the group --NR⁶ R⁷ of R⁵ and in theevent that R⁶ and R⁷ are equal to hydrogen, this hydrogen is replaced,are obtained according to the following DIAGRAM III:

DIAGRAM III ##STR229##

The compoundN-(3-ethoxycarbonylamino-6-methoxypyridine-2-yl)-1,2,3,4-tetrahydro-β-carboline-(D-22550)was obtained according to diagram III:

1st step

1,2,3,4-tetrahydro-β-carboline

In an Erlenmeyer flask 10 g (50 mMol) of tryptamine hydrochloride aredissolved with stirring at 45° C. in 160 ml H₂ O. The mixture is cooledat room temperature and a solution of 5.3 g (56 mMol glyoxylic acidmonohydrate in 12 ml water and then, slowly, a cold solution of 2.8 g(48 mMol) KOH in 14 ml water is added. After stirring for 1 hour theprecipitate formed is filtered and washed with 40 ml H₂ O. The isolatedcompound is transferred to a beaker with 96 ml water. Under stirring13.6 ml conc. hydrochloric acid is added slowly to the product. Themixture is refluxed for 30 minutes, treated again with conc. HCl andkept at boiling temperature for 15 minutes. After cooling to roomtemperature the precipitate is filtered, washed with 12 ml water,dissolved in 160 ml H₂ O and heated to approx. 55° C. under stirring.The solution is adjusted to pH 12 with 20 percent KOH. The resultantsolid compound is then filtered, washed with 160 ml water and dried invacuum.

MP: 205° C.; Yield: 75% of theory

2nd step:

N- (3-nitro-6-methoxy-2-pyridyl-yl)-1,2,3,4-tetrahydro-β-carboline

200 ml acetonitrile and 3.01 g K₂ CO₃ are filled into a flask. Themixture is cooled with an ice-sodium chloride mixture and 2.5 g (14.5mMol) 1,2,3,4-tetrahydro-β-carboline and 2.71 g (14.5 mMol)2-chloro-3-nitro-methoxypyridine are added. This is allowed to come toroom temperature with stirring and heated to reflux temperature for 2hours. The reaction mixture is evaporated in vacuum and the residue istreated with 150 ml H₂ O. The insoluble residue is recrystallised fromethanol.

MP: 218-220° C.; Yield: 89% of theory

3rd step:

N-(3-ethoxycarbonylamino-6-methoxypyridine-2-yl)-1,2,3,4-tetrahydro-β-carboline

4 g (12.3 mMolN-(3-nitro-6-methoxypyridine-2-yl-1,2,3,4-tetrahydro-β-carboline areadded with stirring to a three-necked flask with 200 ml anhydrousethanol. 2 g sodium borohydride and 0.5 g palladium charcoal are addedunder a nitrogen atmosphere. The mixture is refluxed for 2 hours withfurther nitrogen gassing. It is then cooled to 10° C. and 4.07 g (37mmol) chloroformic acid ethyl ester are added dropwise. This is stirredfor 2 hours at 30° C., then cooled to 15° C., filtered and concentrated.The residue is purified by column chromatography on silica gel with amixture of petroleum ether/diisopropyl ether 50/50 (V/V). The residuerecrystallised from petroleum ether/dichloromethane (95:5 (V/V)).

MP: 125° C.; Yield: 42% of theory.

General instructions for the preparation of compounds of general formula1 according to diagram III

Tryptamine hydrochloride is dissolved in water in a flask with heating.Glyoxylic acid monohydrate and a solution of an inorganic base such asNaOH, KOH, LiOH or Ba (OH) 2 are added. After the reaction theprecipitate formed is filtered off and washed. The precipitate is heatedin an inorganic acid such as hydrochloric acid or sulfuric acid, moreconc. hydrochloric acid is added and the mixture is refluxed for sometime. After cooling, the precipitate formed is filtered, washed anddissolved again in H₂ O with stirring. The pH is adjusted to pH 12 with20 percent KOH and the formed 1,2,3,4-tetrahydro-β-carboline isfiltered.

The 1,2,3,4-tetrahydro-β-carboline formed in this manner is heated underreflux for 1-3 hours with commercially available2-chloro-3-nitro-6-methoxypyridine and a base, for example alkali metalcarbonates or alkali hydrogen carbonates in an organic solvent, such asacetonitrile, propionitrile, THF, diethylether or dioxan. Afterevaporation of the solvent, the residue is diluted with water and theinsoluble residue is recrystallised from ethanol.

Product obtained according to the above instructions is reduced in amanner known per se; here:N-(3-nitro-6-methoxy-pyridine-2-yl)-1,2,3,4-tetrahydro-β-carboline isdissolved in absolute ethanol and treated in a nitrogen atmosphere withsodium borohydride and Pd-C as catalyst. The mixture is refluxed for 1-4hours. After cooling, the chloroformic acid ester is added, in this casechloroformic acid ethyl ester, and stirred for further 1-4 hours. Afterfiltration and evaporation of the solvent the residue is purified bycolumn chromatography on silica gel with a mixture of petroleumether/diisopropyl ether 50:50 (V/V) and recrystallised from petroleumether/dichloromethane.

The following examples were synthesised according to the aboveinstructions:

N-(6-amino-5-ethoxycarbonylamino-(-2-pyridyl))-1,2,3,4-tetrahydro-β-carboline(D-22559)

MP: 191° C.; Yield: 40% of theory

Elementary analysis

    ______________________________________                                        C         calc.  64.94       found                                                                              65.05                                         H calc. 6.02 found 6.01                                                       H calc. 19.93 found 19.79                                                   ______________________________________                                    

1-methyl-N-(3-nitro-6-methoxy-(2-pyridyl))-1,2,3,4-tetrahydro-β-carboline(D-23716)

MP: 178-179° C.; Yield: 61% of theory;

1-methyl-N-(5-nitro-6-amino-(2-pyridyl))-1,2,3,4-tetrahydro-β-carboline(D-23706)

MP: 192-194° C.; Yield: 65.5% of theory

The synthesis of the intermediate1-methyl-1,2,3,4-tetrahydro-β-carboline is carried out according to theconventional method of the Pictet-Spengler reaction from tryptamine andacetaldehyde according to the following literature:

Lit.

A. M. Jackson, A. H. Smith, Tetrahedron 24, 403 (1968) and G. Buchi, K.B. Matsumoto, H. Nishimura, J. Aver. Chem. Soc. 93, 3299 (1971):

Spath and Lederer, Chem. Ber. 63, 2101 (1930): Hahn et al. Ann. 520, 107(1935); Chem. Ber. 71, 2163 (1938), 2192 (1938)

The compounds of general formula 1 with G=(i) can also be obtainedaccording to the synthesis scheme of diagram IV, where:

W=CH

X=CH

Y=a single bond,

in such a manner that the heterocyclic system is directly associatedwith the group ##STR230##

DIAGRAM IV ##STR231##

The compoundN-(5-ethoxycarbonylamino-6-amino-(2-pyridyl))-2-(indole-3-yl)ethylamine(D-22191) was, for example, obtained according to the above diagram IV.

Instructions for reaction:

1st step: 3 g (18.7 mMol) tryptamine, 3.25 g (18.7 mMol)2-amino-3-nitro-6-chloropyridine and 2.6 g K₂ CO₃ are heated in 300 mlacetonitrile in a flask for 1 hour under reflux. The solvent is removedunder reduced pressure, the residue is diluted with water and extractedwith dichloromethane. The dichloromethane extracts are dried withanhydrous sodium sulfate, filtered and concentrated. The residue ispurified by column chromatography on silica gel with a mixture ofdichloromethane/ethanol 95:5 (V/V). and recrystallised in absol.ethanol. MP: 196° C., yield 72% of theory.

2nd step: The reduction of the nitro group and the subsequent reactionwith chloroformic acid ethyl ester or chloroformic acid phenyl ester iscarried out according to the general synthesis instructions to preparecompounds of general formula 1 according to diagram III (step 3) on p.71.

Apart from acetonitrile it is also possible to use dioxan, THF,dimethylformamide and isopropanol as solvents for the 1st step. Apartfrom K₂ CO₃ it is also possible to use Na₂ CO₃, NaHCO₃, triethylamine orbasic ion exchanges as acid catchers.

Apart from EtOH it is also possible to use methanol, isopropanol ordioxan as solvents in the 2nd step (reduction step).

In a variant of diagram IV, 2-chloro-3-nitro-6-methoxypyridine was usedfor the condensation with corresponding "indole-3-yl-alkylamines" (1ststep) instead of 2-amino-3-nitro-6-chloropyridine, which is explained inconnection with the preparation of the final compound D-23202 on thebasis of the following synthesis Scheme. ##STR232##

The condensation reaction of 2-(l-methylindole-3-yl)isopropylamine with2-chloro-3-nitro-6-methoxypyridine in acetonitrile (1st step) and K₂ CO₃was carried out by analogy with the instructions on page 69 (there step2) applying to the compound D-22550. The 2nd step with NaBH₄ /Pd-C andthe subsequent reaction with chloroformic acid ethyl ester occurred byanalogy to the instructions for the synthesis of D-22550 according tostep 3 therein.

According to the above general instructions for the synthesis of newindole derivatives according to diagram IV the following compounds weresynthesised which are listed in the following summary, quoting theircode numbers (D-numbers) and the corresponding chemical designation.

The following table 3 shows the structures of these compounds, theirmelting points from general formula 1 and the substituents Y-G, W, X,R¹, R² and R³ :

    ______________________________________                                        D-22192 N-(3-ethoxycarbonylamino-6-methoxy(2-pyridyl))-2-                        (indole-3-yl)ethylamine                                                      D-22556 N-(3-phenoxycarbonylamino-6-methoxy(2-pyridyl))-2-                     (indole-3-yl)ethylamine                                                      D-22702 N-(3-ethoxycarbonylamino-6-methoxy(2-pyridyl))--3-                     (indole-3-yl)propylamine                                                     D-22706 N-(3-ethoxycarbonylamino-6-methoxy(2-pyridyl))-2-                      (1-benzyl-indole-3-yl)isopropylamine                                         D-22948 N-(3-ethoxycarbonylamino-6-methoxy(2-pyridyl))-2-                      [1-(4-fluorobenzyl-indole-3-yl)ethylamine                                    D-22949 N-(5-ethoxycarbonylamino-6-amino(2-pyridyl))-2-                        [1-(4-fluorobenzyl-indole-3-yl)ethylamine maleate                            D-22950 N-(5-ethoxycarbonylamino-6-amino(2-pyridyl))-3-                        (indole-3-yl)propylamine maleate                                             D-23203 N-(5-ethoxycarbonylamino-6-amino(2-pyridyl))-2-                        (1-benzylindole-3-yl)ethylamine maleate                                      D-23201 N-(3-nitro-6-methoxy(2-pyridyl))-2-(1-benzyl-                          indole-3-yl)ethylamine                                                       D-23205 N-(5-ethoxycarbonylamino(2-pyridyl))-2-(1-                             benzylindole-3-yl)isopropylamine                                             D-23204 N-(5-ethoxycarbonylamino-6-amino(2-pyridyl))-3-                        [1-(4-fluorobenzyl)indole-3-yl]propylamine                                   D-23715 N-(5-ethoxycarbonylamino-6-amino(2-pyridyl))-2-                        (5-chloroindole-3-yl)ethylamine maleate                                      D-22193 N-[1-(3-ethoxycarbonylamino-6-methoxy-(2-pyridyl))                     piperidine-4-yl]-3-(indole-3-yl)propionamide                                 D-22194 N-[1-(3-ethoxycarbonylamino-6-methoxy-(2-pyridyl))-2-                  piperidine-4-yl](indole-3-yl)acetamide                                       D-22987 N-(5-ethoxycarbonylamino-6-amino-(2-pyridyl))-2-                       (1-methylindole-3-yl)isopropylamine maleate                                  D-22988 N-(3-ethoxycarbonylamino-6-amino-(2-pyridyl))-2-                       (-methylindole-3-yl)ethylamine                                               D-22989 N-(3-ethoxycarbonylamino-6-methoxy-(2-pyridyl))-2-                     (5-chloroindole-3-yl)ethylamine                                              D-22990 N-(5-ethoxycarbonylamino-6-amino-(2-pyridyl))-2-                       (1-methylindole-3-yl)ethylamine                                              D-22991 N-(5-nitro-6-amino-(2-pyridyl))-2-(1-benzylindole-                     3-yl)ethylamine                                                              D-22992 N-(3-ethoxycarbonylamino-6-methoxy-(2-pyridyl))-2-                     (1-benzylindole-3-yl)ethylamine                                              D-22993 N-(3-ethoxycarbonylamino-6-methoxy-(2-pyridyl)-3-                      [1-(4-fluorobenzyl)indole-3-yl)propylamine                                   D-23202 N-(3-ethoxycarbonylamino-6-methoxy-(2-pyridyl))-2-                     (1-methylindole-3-yl]isopropylamine                                          D-22195 N-[1-(5-ethoxycarbonylamino-6-amino-(2-pyridyl))-4-                    piperidyl]-2-(indole-3-yl)propionamide                                       D-24325 N-[1-(5-ethoxycarbonylamino-6-amino-(2-pyridyl))-4-                    piperidyl](indole-3-yl]acetamide                                             D-22188 N-(5-nitro-6amino-(2-pyridyl))-2-(indole-3-                            yl)ethylamine                                                                D-22189 N-[1-(5-nitro-6-amino-(2-pyridyl))-4-piperidyl]-3-                     (indole-3-yl)propionamide                                                    D-22190 N-[1-(5-nitro-6-amino-(2-pyridyl))-4-piperidyl]-(indole-                      3-yl)acetamide                                                        D-22699 N-(3-nitro-6-methoxy-(2-pyridyl))-3-(indole-3-                         yl)propylamine                                                               D-22700 N-(5-nitro-6-amino-(2-pyridyl))-3-(indole-3-                           yl)propylamine                                                               D-22703 N-(3-nitro-6-methoxy-(2-pyridyl))-2-(1-benzyl-                         indole-3-yl)isopropylamine                                                   D-22704 N-(3-nitro-6-methoxy-(2-pyridyl))-2-[1-(4-                             fluorobenzyl)indole-3-yl]ethylamine                                          D-22705 N-(3-nitro-6-amino-(2-pyridyl))-2-[1-(4-fluoro-                        benzyl)indole-3-yl]ethylamine                                                D-22707 N(5-nitro-6-amino-(2-pyridyl))-2-(1-methylindole-                      3-yl)isopropylamine                                                          D-22984 N-(3-nitro-6-methoxy-(2-pyridyl))-2-(1-methyl.                         indole-3-yl)ethylamine                                                       D-22947 N(5-nitro-6-amino-(2-pyridyl))-2-(1-methylindole-                      3-yl)ethylamine                                                              D-22985 N-(3-nitro-6-methoxy-(2-pyridyl))-2-(5-                                chloroindole-3-yl)ethylamine                                                 D-22986 N-(5-nitro-6-amino-(2-pyridyl))-2-(5-chloroindole-                     3-yl)ethylamine                                                            ______________________________________                                    

                                      TABLE 3                                     __________________________________________________________________________    Novel indole compounds according to reaction diagram IV                       1  STR233##                                                                   New indole derivatives according to reaction diagram IV                       D    Y--G                   W  X  R.sup.1      R.sup.2                                                                          R.sup.3                                                                         Fp[°C.]            __________________________________________________________________________      22191                                                                                                                           2  CH CH H H H 46                                                             (deliquesce)                 - 22192                                                                                                                        3  CH CH H H H 184                                                              - 22193                                                                     4  CH CH H H H  92                                                              - 24325                                                                     5  CH CH H H H                                                                232-234                      - 22194                                                                                                                        6  CH CH H H H 144                                                              - 22195                                                                     7  CH CH H H H 208                                                              - 22556                                                                     8  CH CH H H H 131                                                              - 22702                                                                     9  CH CH H H H  53                                                            (deliquesce)                 - 22706                                                                                                                        0  CH CH ##                                                                   2  H H 166                   - 22948                                                                                                                        1  CH CH ##                                                                   3  H H 113                   - 22949                                                                                                                        4  CH CH ##                                                                   3  H H 175                   - 22950 (Maleat)                                                                                                               5  CH CH H H H 138                                                              - 22987 (Maleat)                                                            6  CH CH CH.sub.3 H H                                                         110                          - 22988                                                                                                                        7  CH CH CH.sub.3 H H                                                         120-122                      - 22989                                                                                                                        7  CH CH H 5-Cl H  90                                                         (deliquesce)                 - 22990 (Maleat)                                                                                                               8  CH CH CH.sub.3 H H                                                         168-170                      - 22992                                                                                                                        9  CH CH ##                                                                   2  H H 114-116                                                                  - 22993                                                                     0  CH CH ##                                                                   3  H H  90-92                                                                 (deliquesce)                 - 23202                                                                                                                        1  CH CH CH.sub.3 H H                                                          50 (deliquesce)                                                                - 23203 (Maleat)                                                            2  CH CH ##                                                                   2  H H 168-170                                                                  - 23205 (Maleat)                                                            3  CH CH ##                                                                   2  H H 144-146                                                                  - 23204 (Maleat)                                                            4  CH CH ##                                                                   3  H H  90 (deliquesce                                                        )                            - 23715                                                                                                                        4  CH CH H 5-Cl H                                                             182-184                      - 22991                                                                                                                        5  CH CH ##                                                                   2  H H 158-160                                                                  - 23201                                                                     6  CH CH ##                                                                   2  H H 116-118                                                                  - 22188                                                                     7  CH CH H H H 196                                                              - 22189                                                                     8  CH CH H H H 192                                                              - 22190                                                                     9  CH CH H H H 200                                                              - 22699                                                                     0  CH CH H H H 113                                                              - 22700                                                                     1  CH CH H H H 120                                                              - 22703                                                                     2  CH CH ##                                                                   2  H H 128                   - 22704                                                                                                                        3  CH CH ##                                                                   3  H H 138                   - 22705                                                                                                                        5  CH CH ##                                                                   3  H H 149                   - 22707                                                                                                                        4  CH CH CH.sub.3 H H                                                          50 (deliquesce)                                                                - 22984                                                                     5  CH CH CH.sub.3 H H                                                         244-246                      - 22947                                                                                                                        5  CH CH CH.sub.3 H H                                                         140                          - 22985                                                                                                                        5  CH CH H 5-Cl H                                                             180-182                      - 22986                                                                                                                        5  CH CH H 5-Cl H                                                             218-220                      - 22687                                                                                                                        6  CH CH ##                                                                   3  H H 133#               __________________________________________________________________________

Starting material for the compounds of general formula 1 (intermediatesynthesis) synthesised in table 3 according to reaction diagram IV:

    ______________________________________                                        Final compound Starting material [D]                                          ______________________________________                                        D-23715        22986                                                            D-23203 22991                                                                 D-22705 22949                                                                 D-22990 22947                                                                 D-22950 22700                                                                 D-22987 22707                                                                 D-22191 22188                                                                 D-22993 22704                                                                 D-22988 22984                                                                 D-22556, D-22192 22985                                                        D-22992 23201                                                                 D-22702 22699                                                                 D-22195 22189                                                                 D-24325 22190                                                               ______________________________________                                    

The 2-(1-methylindole-3-yl)isopropylamine used, for example, for thefinal compound D-23202 can be synthesised according to the followingreaction scheme: ##STR287## Instructions:

1st step: A solution of 9 g (56.5 mMol) 1-methyl-indole-3-carbaldehydeand 6.1 g (79 mMol) ammonium acetate in 200 ml nitroethane is refluxedwith stirring for 2 hours. After substantial evaporation of the solventan orange-coloured precipitate of1-(1-methyl-1H-indole-3-yl)-2-nitropropene precipitates out aftercooling.

Yield: 86% of theory; MP: 132-134° C.

2nd step: A suspension of 3.6 g LiAlH₄ in 200 ml anhydroustetrahydrofuran (THF) is mixed dropwise with a solution of 5.4 g1-(1-methyl-1H-indole-3-yl)-2-nitropropene in 100 ml THF. The mixture isheated to reflux for 1 hour, then cooled, excess of lithium aluminiumhydride is slowly destroyed by adding 150 ml iced water and theresultant mixture is extracted with dichloromethane. The organic phaseis dried with anhydrous sodium sulfate and evaporated in vacuum. Ayellow oil is obtained that is dried in vacuum and immediately used forthe condensation reaction with 2-chloro-3-nitro-6-methoxypyridine.

Yield: 85% of theory.

The compounds of general formula 1 from the 1H-indazole series withG=(i) can also be prepared according to the following diagram V:

DIAGRAM V: ##STR288##

According to the above diagram V, the compoundN-(4-pyridyl)-2-[1-(4-fluorobenzyl)-1H-indazole-3-yloxy]acetamide(D-23591) was for example obtained as follows:

A suspension of 1.0 g (3.33 mol)[[1-(4-fluorophenylmethyl)-1H-indazole-3-yl]oxy]-acetic acid in 20 mlmethylene chloride was mixed with stirring with a suspension of 0.85(3.33 mMol) 2-chloro-1-methylpyridinium-iodide, 1.2 ml triethylamine and0.31 g (3.33 mMol) 4-aminopyridine in 30 ml methylene chloride andheated to reflux for 4 hours. After cooling, the reaction mixture isextracted three times with 50 ml H₂ O and the methylene chloridesolution is dried over anhydrous sodium sulfate. Evaporation thesolution yields a precipitate which is purified on a silica gel column(column chromatography on silica gel with a mixture toluene(chloroform/methanol 2:1:0.5).

Yield: 0.82 g (65.4% of theory); Melting point: 136° C.-139° C.

New 1H-indazole derivatives were synthesized according to the aboveinstructions and by analogy with the general method of procedureaccording to diagram I, these are listed in the following summary,quoting their code numbers (D-numbers) and the corresponding chemicaldesignation. The following table 4 shows the structures of thesecompounds and their melting points from the general formula 1 and thesubstituents Y-G, W, X, R¹, R² and R³ :

    ______________________________________                                        D-23557 N-(4-pyridyl)-2-[1-(4-chlorobenzyl)-5-methoxy-                           1H-indazole-3-yloxy]acetamide                                                D-23590 N-(4-pyridyl)-2-[1-(4-chlorobenzyl)-1H-indazole                        3-yloxy]acetamide                                                            D-23592 N-(3-pyridyl)-2-[1-(4-chlorobenzyl)-5-methoxy-                         1H-indazole-3-yloxy]acetamide                                                D-23593 N-(2-methyl-4-quinolyl)-2-[1-(4-chlorobenzyl)-5-                       methoxy-1H-indazole-3-yloxy]acetamide                                        D-23686 N-(3-pyridyl)-2-[1-(4-fluorobenzyl)                                    1H-indazole-3-yloxy]acetamide                                                D-23687 N-(2-nitro-3-pyridyl)-2-[1-(4-fluorobenzyl)-1H-                        indazole-3-yloxy]acetamide                                                   D-23758 N-(3-pyridyl)-2-[1-(4-chlorobenzyl)-1H-                                indazole-3-yloxy]acetamide                                                   D-23760 N-(3-pyridyl)-2-[1-(4-fluorobenzyl)-5-methoxy-                         1H-indazole-3-yloxy]acetamide                                                D-23761 N-(6-amino-2-pyridyl)-2-[1-(4-chlorobenzyl)-1H-                        indazole-3-yloxy]acetamide                                                   D-23778 N-(2-nitro-3-pyridyl)-2-[1-(4-chlorobenzyl)-1H-                        indazole-3-yloxy]acetamide                                                   D-23779 N-(4-pyridyl)-2-[1-(4-fluorobenzyl)-5-methoxy-                         1H-indazole-3-yloxy]acetamide                                                D-23781 N-(4-pyridyl)-2-[1-(4-fluorobenzyl)-5-nitro-1H-                        indazole-3-yloxy]acetamide                                                   D-23782 N-(5-methoxycarbonyl-2-pyridyl)-2-[1-(4-                               fluorobenzyl)-1H-indazole-3-yloxy]acetamide                                  D-23783 N-(6-amino-2-pyridyl)-2-[1-(4-fluorobenzyl-                            indazole-3-yloxy]acetamide                                                   D-23828 N-(4-pyridyl)-2-[1-(4-chlorobenzyl)-5-nitro-1H-                        indazole-3-yloxy]acetamide                                                   D-23829 N-(6-amino-2-pyridyl)-2-[1-(4-chlorobenzyl)-5-                         methoxy-1H-indazole-3-yloxy]acetamide                                        D-23830 N-(5-methoxycarbonyl-2-pyridyl)-2-[1-(4-                               fluorobenzyl-5-methoxy-1H-indazole-3-                                         yloxy]acetamide                                                              D-23861 N-(6-amino-2-pyridyl)-2-[1-(4-fluorobenzyl)-5-                         methoxy-1H-indazole-3-yloxy]acetamide                                        D-23874 N-(5-methoxycarbonyl-2-pyridyl)-2-[1-(4-                               chlorobenzyl-5-methoxy-1H-indazole-3-                                         yloxy]acetamide                                                              D-23915 N-(2-nitro-3-pyridyl)-2-[1-(4-fluorobenzyl)-5-                         methoxy-1H-indazole-3-yloxy]acetamide                                        D-23930 N-(5-methoxycarbonyl-2-pyridyl)-2-[1-(4-                               chlorobenzyl-1H-indazole-3-yloxy]acetamide                                 ______________________________________                                    

                                      TABLE 4                                     __________________________________________________________________________    Novel 1H-indazole derivatives according to diagram V                          7  STR289##                                                                   D   --Y--G              R.sup.1      X W R.sup.3                                                                         R.sup.2                                                                            Fp.                           __________________________________________________________________________      23557                                                                                                                       8  STR290##                                                                   9  N CH H 5-O--CH.sub.3                                                       97-99° C.                 - 23590                                                                                                                    8  STR292##                                                                   9  N CH H H 158-161.degree                                                    . C.                             - 23591                                                                                                                    8  STR294##                                                                   3  N CH H H 136-139.degree                                                    . C.                             - 23592                                                                                                                    0  STR296##                                                                   9  N CH H 5-O--CH.sub.3                                                       177-178° C.                                                              - 23593                                                                     1  STR298##                                                                   9  N CH H 5-O--CH.sub.3                                                       152-160° C.                                                              - 23686                                                                     0  STR300##                                                                   3  N CH H H Ol                   - 23687                                                                                                                    2  STR302##                                                                   3  N CH H H 158-160.degree                                                    . C.                             - 23758                                                                                                                    0  STR304##                                                                   9  N CH H H 148-150.degree                                                    . C.                             - 23760                                                                                                                    0  STR306##                                                                   3  N CH H 5-O--CH.sub.3                                                       159-160° C.                                                              - 23761                                                                     3  STR308##                                                                   9  N CH H H 170-171.degree                                                    . C.                             - 23778                                                                                                                    2  STR310##                                                                   9  N CH H H 154-156.degree                                                    . C.                             - 23779                                                                                                                    8  STR312##                                                                   3  N CH H 5-O--CH.sub.3                                                       157-158° C.                                                              - 23781                                                                     8  STR314##                                                                   3  N CH H 5-NO.sub.2                                                          176-178° C.                                                              - 23782                                                                     4  STR316##                                                                   3  N CH H H 160.5-161.5.de                                                    gree.                            - 23783                                                                                                                    3  STR318##                                                                   3  N CH H H 193.5-194.5.de                                                    gree.                            - 23828                                                                                                                    8  STR320##                                                                   9  N CH H 5-NO.sub.2                                                          207.5-208° C.                                                            - 23829                                                                     3  STR322##                                                                   9  N CH H 5-O--CH.sub.3                                                       178-180° C.                                                              - 23830                                                                     4  STR324##                                                                   3  N CH H 5-O--CH.sub.3                                                       160-160.5° C.                                                            - 23861                                                                     3  STR326##                                                                   3  N CH H 5-O--CH.sub.3                                                       157.5-158° C.                                                            - 23874                                                                     4  STR328##                                                                   9  N CH H 5-O--CH.sub.3                                                       159-160° C.                                                              - 23915                                                                     2  STR330##                                                                   3  N CH H 5-O--CH.sub.3                                                       180-181° C.                                                              - 23930                                                                     4  STR332##                                                                   9  N CH H H 169-170.degree                                                    . C.                          __________________________________________________________________________

Starting compounds for reactions according to diagram V

The starting substances according to the reactions described for diagramV can be prepared from the 1-benzyl-1H-indazole-3-ols published by L.Baiochchi et al. Synthesis 1978, 633 and thus known to the literature byreaction with chloroacetic acid ethyl ester in DMF with K₂ CO₃ and alsoin aqueous sodium hydroxide solution at room temperature or elevatedtemperature up to 80° C. The (1-benzyl-1H-indazole-3-yl)oxyacetic acidethyl esters primarily formed thereby are reacted with sodium hydroxidesolution at 50° C. in an ethanol/water solvent mixture and thecorresponding (1-benzyl-1H-indazole-3-yl)oxyacetic acids precipitatedout by acidulation with dilute hydrochloric acid.

In addition, the compounds of general formula 1 with G=(ii) can beobtained according to the synthesis path of diagram VI, where

W=CH

X=N

Y=O

DIAGRAM VI ##STR334##

The compounds1-(4-chlorobenzyl)-3-[2-(1-methylpyrrolidine-2-yl)-ethoxy]-1H-indazole(D-22591) and 1-(4-chlorobenzyl)-3-(1-methyl-azepan-4-yloxy)-1H-indazole(D-22175) were obtained according to the above diagram VI:

Instructions:

4,1-(4-chlorobenzyl)-3-[2-(1-methylpyrrolidine-2-yl)-ethoxy]-1H-indazole(1)and 1-(4-chlorobenzyl)-3-(l-methyl-azepan-4-yloxy)-1H-indazole (2)

A solution of 3.75 g (29 mMol) 1-methylazepan-4-ol in 15 ml anhydrousTHF was added dropwise to a solution of 5 g (19 mMol)1-(4-chlorobenzyl)-1H-indazole-3-one in 150 ml anhyclrous THF at 23° C.with stirring. After stirring for approx. 10 min. at room temperature7.6 g (29 mMol) triphenylphosphine and a solution of 5.1 g (29 mMol)azodicarboxylic acid ethyl ester in 10 ml anhydrous THF was thenimmediately added dropwise. After stirring for 5 hours at roomtemperature the solvent was removed at reduced pressure. The residue waspurified by flash chromatography in the first with a mixture of CH₂ Cl₂/aceton (80:20), whereby triphenylphosphine oxide and small amounts ofunreacted 1-(4-chlorobenzyl)-1H-indazole-3-one were eluted. Elution witha mixture of CH₂ Cl₂ /methanol (80:20) yielded a mixture consisting ofthe two title compounds 1 and 2:1-(4-chlorobenzyl)-3-[2-(1-methylpyrrolidine-2-yl)-ethoxy]-1H-indazole(1) and 1-(4-chlorobenzyl)-3-[(1-methylazepan-4-yl)oxy]-1H-indazole (2).##STR335## General instructions for the preparation of compounds ofgeneral formula 1 for G=(ii)

A solution of the amine is added dropwise at room temperature to astirred solution of the indazole derivative in an organic solvent, suchas THF, dioxan, DMF or DMA. This mixture is briefly stirred beforeadding triphenylphosphine and azodicarboxylic acid ester in THF. Afterthe end of the reaction the solvent is removed under reduced pressure.The residue is purified by column chromatography with a mixture ofmethylene chloride/acetone (80:20).

The following compounds were synthesized according to the aboveinstructions for the synthesis of novel indazole derivatives accordingto diagram VI and according to the example set out as well as to theGeneral Instructions, these are set out in the following summary,quoting their code numbers (D-numbers) and the corresponding chemicaldesignation. The following table 5 shows the structures of thesecompounds and their melting points from the general formula 1 and thesubstituents Y-G, W, X, R¹, R², R³ :

    ______________________________________                                        D-21963 1-(4-fluorobenzyl)-3-(1-methylazepan-4-yloxy)-                           1H-indazole                                                                  D-22055 1-(4-fluorobenzyl)-3-(1-methyl-4-                                      piperidyloxy)-1H-indazole                                                    D-22105 1-(4-chlorobenzyl)-3-(1-methyl-4-piperidyl-                            oxy)-1H-indazole                                                             D-23172 1-(4-chlorobenzyl)-3-[2-(1-methylpyrolidine-2-                         yl)-ethoxy]-5-nitro-1H-indazole                                              D-23173 1-(4-chlorobenzyl)-3-(1-methylazepan-4-yloxy)-                         5-nitro-1H-indazole                                                          D-22453 1-(4-fluorobenzyl)-3-[3-(N-diethyl amino)-                             propoxy]-1H-indazole                                                         D-22470 1-(3-pyridylmethyl)-3-[3-(N-diethylamino)-                             propoxy]-1H-indazole                                                         D-22585 1-(4-fluorobenzyl)-3-[3-(N-dimethylamino)-                             propoxy]-1H-indazole hydrochloride                                           D-22627 1-(2-quinolylmethyl)-3-[3-(N-dimethylamino)-                           propoxy]-1H-indazole                                                         D-22634 1-(2-quinolylmethyl)-3-[3-(N-dimethylamino)-                           propoxy]-1H-indazole hydrochloride                                           D-22768 1-(4-fluorobenzyl)-3-[3-(N-dimethylamino)-                             propoxy]-1H-indazole maleate                                                 D-22814 1-(4-chlorobenzyl)-3-[3-(N-dimethylamino).                             propoxy]-1H-indazole                                                         D-22890 1-(4-chlorobenzyl)-3-[3-N-diethylamino)-                               propoxy]-5-nitro-1H-indazole hydrochloride                                   D-22895 1-(4-chlorobenzyl)-3-[3-(N-diethylamino)-                              propoxy]-1H-indazole                                                         D-22952 1-(4-chlorobenzyl)-3-[3-(N-diethylamino)-                              propoxy]-5-[(4-methoxyphenyl)-methylcarbonyl-                                 amino]-1H-indazole hydrochloride                                             D-22953 1-(4-chlorobenzyl)-3-[3-(N-diethylamino)-                              propoxy]-5-[(4-methoxyphenyl)-carbonylamino]-                                 1H-indazole hydrochloride                                                    D-22954 1-(4-chlorobenzyl)-3-[3-(N-diethylamino)-                              propoxy)-5-[(4-bromophenoxy)-carbonylamino]-1H-                               indazole hydrochloride                                                       D-23097 1-(4-fluorobenzyl)-3-[3-(N-diethylamino)-                              propoxy]-5-(ethoxycarbonylamino)-1H-indazole                                  hydrochloride                                                                D-23174 1-(4-fluorobenzyl)-3-(3-(N-dimethylamino)-                             propoxy]-5-nitro-1H-indazole hydrochloride                                   D-23225 1-(4-chlorobenzyl)-3-[3-(N-diethylamino)-                              propoxy]-5-(cyclohexyloxycarbonylamino]-1H-                                   indazole hydrochloride                                                       D-23236 1-(4-fluorobenzyl)-3-[3-(N-diethylamino)-                              propoxy]-5-(cyclohexyloxycarbonylamino)-1H-                                   indazole hydrochloride                                                       D-23308 1-(4-fluorobenzyl)-3-[3-N-dimethylamino)-                              propoxy]-5-methoxy-1H-indazole                                               D-23309 1-(4-chlorobenzyl)-3-(3-(N-diethylamino)-                              propoxyl-5-(ethoxycarbonylamino)-1H-indazole                                  hydrochloride                                                                D-23517 1-(4-fluorobenzyl)-3-[3-(N-diethylamino)-                              propoxy]-5-(fluoroenylmethyloxycarbonylamino)-                                1H-indazole hydrochloride                                                    D-23584 1-(4-fluorobenzyl)-3-[3-(N-diethylamino)-                              propoxy]-5-(cyclopentyloxycarbonylamino)-1H-                                  indazole hydrochloride                                                     ______________________________________                                    

                                      TABLE 5                                     __________________________________________________________________________    Novel indazole derivatives according to diagram VI                            4  STR336##                                                                   D   --Y--G          R.sup.1     X  W R.sup.3                                                                          R.sup.2          Fp.                  __________________________________________________________________________      21963                                                                                                                                5  STR337##                                                                   3  N CH H H oil                                                                 - 22055                                                                     6  STR339##                                                                   3  N CH H H 140-                                                              144° C.                                                                  - 22105                                                                     7  STR341##                                                                   9  N CH H H                                                                   82° C.                                                                   - 23173                                                                     5  STR343##                                                                   9  N CH H                                                                     5-NO.sub.2                                                                    75-78° C.        - 23172                                                                                                                             8  STR345##                                                                   9  N CH H                                                                     5-NO.sub.2 171-                                                               174° C.                                                                  - 22175                                                                     5  STR347##                                                                   9  N CH H H oil                                                                 - 22591                                                                     9  STR349##                                                                   9  N CH H H oil                                                                 - 22453                                                                     0  STR351##                                                                   3  N CH H H                                                                   102° C.                                                                  - 22470                                                                     0  STR353##                                                                   1  N CH H H oil                                                                 - 22585                                                                     2  STR355##                                                                   3  N CH H H                                                                   103° C.                                                                  - 22768                                                                     3  STR357##                                                                   3  N CH H H                                                                   85° C.                                                                   - 22814                                                                     4  STR359##                                                                   9  N CH H H oil                                                                 - 22890                                                                     5  STR361##                                                                   9  N CH H                                                                     5-NO.sub.2 134-                                                               138° C.                                                                  - 22895                                                                     0  STR363##                                                                   9  N CH H H oil                                                                 - 22952                                                                     5  STR365##                                                                   9  N CH H                                                                     6  147- 149.degre                                                             e. C.                   - 22953                                                                                                                             5  STR368##                                                                   9  N CH H                                                                     6  170- 172.degre                                                             e. C.                   - 22954                                                                                                                             5  STR371##                                                                   9  N CH H                                                                     7  178- 0  C.                                                                   - 23097                                                                     5  STR374##                                                                   3  N CH H                                                                     8   99-102.degree                                                             . C.                    - 22627                                                                                                                             5   N CH H H                                                                  175° C.                                                                  - 22634                                                                     9   N CH H H                                                                  152° C.                                                                  - 23174                                                                     5  STR379##                                                                   3  N CH H                                                                     5-NO.sub.2 150-                                                               153° C.                                                                  - 23225                                                                     5  STR381##                                                                   9  N CH H                                                                     0  181°                                                                C.                      - 23236                                                                                                                             5  STR384##                                                                   3  N CH H                                                                     0  159°                                                                C.                      - 23308                                                                                                                             0  STR387##                                                                   3  N CH H                                                                     5-O--CH.sub.3                                                                 89° C.                                                                   - 23309                                                                     5  STR389##                                                                   9  N CH H                                                                     8   95°                                                                C.                      - 23517                                                                                                                             5  STR392##                                                                   3  N CH H                                                                     1  142°                                                                C.                      - 23584                                                                                                                             5  STR395##                                                                   3  N CH H                                                                     2  oil397##          __________________________________________________________________________

What is claimed is:
 1. A compound of formula 1: ##STR398## wherein R¹represents hydrogen, a straight-chained (C₁ -C₆)alkyl group, which isoptionally substituted by phenyl or halogen-substituted phenyl;R²represents hydrogen or a branched (C₁ -C₆) alkyl group; R³ representshydrogen; W represents CH; X represents CH; Y represents a single bondin such a manner that the heterocyclic system is directly associatedwith the group ##STR399## wherein n is 1-6 and R⁴ represents hydrogen; Grepresents ##STR400## wherein m is 1, Z represents O or two hydrogenatoms, R⁵ represents the radical ##STR401## wherein R⁶ representshydrogen and R⁷ represents a pyridine skeleton, which is linked to oneof the ring carbon atoms and is optionally substituted with radicals R⁸and R⁹ which may be identical or different and representstraight-chained (C₁ -C₆) alkyl, (C₁ -C₆)alkoxy, or ethoxycarbonylamino,and wherein ##STR402## may also include one --CH═CH-- unit when n isequal to or greater than two; and pharmaceutically usable acid additionsalts thereof.
 2. N-(4-pyridyl)-[1-(4-fluorobenzyl)indole-3-yl]acetamineand the physiologically acceptable acid addition salts thereof. 3.N-(3-pyridyl)-2-[1-(4-fluorobenzyl)indole-3-yl]ethylamine and thephysiologically acceptable acid addition salts thereof. 4.N-(4-pyridyl)-2-(1-benzyl-2-methyl-5-isopropylindole-3-yl)acetamide, andthe physiologically acceptable acid addition salts thereof. 5.N-(4-pyridyl)-2-(5-isopropyl-1H-indole-3-yl)acetamine and thephysiologically acceptable acid addition salts thereof. 6.N-(2-pyridyl)-2-[1-(4-fluorobenzyl)indole-3-yl]ethylamine, and thephysiologically acceptable acid addition salts thereof. 7.N-(4-pyridyl)-2-[1-(4-fluorobenzyl)6-hydroxyindole-3-yl]acetamide, andthe physiologically acceptable acid addition salts thereof. 8.N-(4,6-dimethyl-2-pyridyl)-3-[1-(4-fluorobenzyl)indole-3-yl)]propenamideand the physiologically acceptable acid addition salts thereof. 9.N-(4-pyridyl)-2-(1-benzylindole-3-yl)ethylamine and the physiologicallyacceptable acid addition salts thereof. 10.N-(3-pyridyl)-3-[1-(4-fluorobenzyl)-indole-3-yl)propylamine and thephysiologically acceptable acid addition salts thereof. 11.N-(4-pyridyl)-3-(1-p-fluorobenzylindole-3-yl)propylamine and thephysiologically acceptable acid addition salts thereof. 12.N-(4-pyridyl)-3-(1-methylindole-3-yl)propylamine and the physiologicallyacceptable acid addition salts thereof. 13.N-(4-pyridyl)-2-[1-(4-fluorobenzyl)indole-3-yl]ethylamine and thephysiologically acceptable acid addition salts thereof. 14.N-(4-pyridyl)-(1-ethylindole-3-yl)acetamide and the physiologicallyacceptable acid addition salts thereof. 15.N-(3-ethoxycarbonylamino-6-methoxy-2-pyridyl)-2-(1-benzylindole-3-yl)ethylamineand the physiologically acceptable acid addition salts thereof. 16.N-(3-ethoxycarbonylamino-6-methoxy-2-pyridyl)-3-(1-(4-fluorobenzyl)indole-3-yl)propylamineand the physiologically acceptable acid addition salts thereof.
 17. Amedicament comprising a compound according to one of claims 2, 3, 5-8 or1 and a physiologically acceptable carrier, diluting agent or auxiliarysubstance.